Abstract
Progesterone receptors (PR) are transcription factors relevant to breast cancer biology. Herein, we describe an N-terminal common docking (CD) domain in PR-B, a motif first described in mitogen-activated protein kinases. Binding studies revealed PR-B interacts with dual-specificity phosphatase 6 (DUSP6) via the CD domain. Mutation of the PR-B CD domain (mCD) attenuated cell cycle progression and expression of PR-B target genes (including STAT5A and Wnt1); mCD PR-B failed to undergo phosphorylation on Ser81, a ck2-dependent site required for expression of these genes. PR-B Ser81 phosphorylation was dependent on binding with DUSP6 and required for recruitment of a transcriptional complex consisting of PR-B, DUSP6 and ck2 to an enhancer region upstream of the Wnt1 promoter. STAT5 was present at this site in the absence or presence of progestin. Furthermore, phospho-Ser81 PR-B was recruited to the STAT5A gene upon progestin treatment, suggestive of a feed-forward mechanism. Inhibition of JAK/STAT-signaling blocked progestin-induced STAT5A and Wnt1 expression. Our studies show that DUSP6 serves as a scaffold for ck2-dependent PR-B Ser81 phosphorylation and subsequent PR-B-specific gene selection in coordination with STAT5. Coregulation of select target genes by PR-B and STAT5 is likely a global mechanism required for growth promoting programs relevant to mammary stem cell biology and cancer.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 8926-8942 |
| Number of pages | 17 |
| Journal | Nucleic acids research |
| Volume | 41 |
| Issue number | 19 |
| DOIs | |
| State | Published - Oct 2013 |
Bibliographical note
Funding Information:National Institutes of Health [T32 CA009138 to C.H., 1K99CA166643-01 to C.H., R01 CA159712 to C.L.]; Department of Defense Breast Cancer Research Program [BC085608 to C.H., BC093529 to T.K.]. Funding for open access charge: NIH K99.
